IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody
Identifieur interne : 000F45 ( Ncbi/Merge ); précédent : 000F44; suivant : 000F46IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody
Auteurs : Shinji Saito [Japon] ; Kaori Sano [Japon] ; Tadaki Suzuki [Japon] ; Akira Ainai [Japon] ; Yuki Taga [Japon] ; Tomonori Ueno [Japon] ; Koshiro Tabata [Japon] ; Kumpei Saito [Japon] ; Yuji Wada [Japon] ; Yuki Ohara [Japon] ; Haruko Takeyama [Japon] ; Takato Odagiri [Japon] ; Tsutomu Kageyama [Japon] ; Kiyoko Ogawa-Goto [Japon] ; Pretty Multihartina [Indonésie] ; Vivi Setiawaty [Indonésie] ; Krisna Nur Andriana Pangesti [Indonésie] ; Hideki Hasegawa [Japon]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2019.
Abstract
Mucosal immunoglobulins comprise mainly secretory IgA antibodies (SIgAs), which are the major contributor to pathogen-specific immune responses in mucosal tissues. These SIgAs are highly heterogeneous in terms of their quaternary structure. A recent report shows that the polymerization status of SIgA defines their functionality in the human upper respiratory mucosa. Higher order polymerization of SIgA (i.e., tetramers) leads to a marked increase in neutralizing activity against influenza viruses. However, the precise molecular mechanisms underlying the effects of SIgA polymerization remain elusive. Here, we developed a method for generating recombinant tetrameric monoclonal SIgAs. We then compared the anti-viral activities of these tetrameric SIgAs, which possessed variable regions identical to that of a broadly neutralizing anti-influenza antibody F045-092 against influenza A viruses, with that of monomeric IgG or IgA. The tetrameric SIgA showed anti-viral inhibitory activity superior to that of other forms only when the antibody exhibits low-affinity binding to the target. By contrast, SIgA tetramerization did not substantially modify anti-viral activity against targets with high-affinity binding. Taken together, the data suggest that tetramerization of SIgA improved target breadth, but not peak potency of antiviral functions of the broadly neutralizing anti-influenza antibody. This phenomenon presumably represents one of the mechanisms by which SIgAs present in human respiratory mucosa prevent infection by antigen-drifted influenza viruses. Understanding the mechanisms involved in cross neutralization of viruses by SIgAs might facilitate the development of vaccine strategies against viral infection of mucosal tissues.
Url:
DOI: 10.1371/journal.ppat.1007427
PubMed: 30605488
PubMed Central: 6317788
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<author><name sortKey="Ogawa Goto, Kiyoko" sort="Ogawa Goto, Kiyoko" uniqKey="Ogawa Goto K" first="Kiyoko" last="Ogawa-Goto">Kiyoko Ogawa-Goto</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody</title>
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<author><name sortKey="Taga, Yuki" sort="Taga, Yuki" uniqKey="Taga Y" first="Yuki" last="Taga">Yuki Taga</name>
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<author><name sortKey="Ueno, Tomonori" sort="Ueno, Tomonori" uniqKey="Ueno T" first="Tomonori" last="Ueno">Tomonori Ueno</name>
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<author><name sortKey="Tabata, Koshiro" sort="Tabata, Koshiro" uniqKey="Tabata K" first="Koshiro" last="Tabata">Koshiro Tabata</name>
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<author><name sortKey="Saito, Kumpei" sort="Saito, Kumpei" uniqKey="Saito K" first="Kumpei" last="Saito">Kumpei Saito</name>
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<author><name sortKey="Wada, Yuji" sort="Wada, Yuji" uniqKey="Wada Y" first="Yuji" last="Wada">Yuji Wada</name>
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</nlm:aff>
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<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo</wicri:regionArea>
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<author><name sortKey="Ohara, Yuki" sort="Ohara, Yuki" uniqKey="Ohara Y" first="Yuki" last="Ohara">Yuki Ohara</name>
<affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan</addr-line>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo</wicri:regionArea>
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</placeName>
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<author><name sortKey="Takeyama, Haruko" sort="Takeyama, Haruko" uniqKey="Takeyama H" first="Haruko" last="Takeyama">Haruko Takeyama</name>
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</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Life Science and Medical Bioscience, Waseda University, Shinjuku, Tokyo</wicri:regionArea>
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<author><name sortKey="Odagiri, Takato" sort="Odagiri, Takato" uniqKey="Odagiri T" first="Takato" last="Odagiri">Takato Odagiri</name>
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</nlm:aff>
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<wicri:regionArea>Influenza Virus Research Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kageyama, Tsutomu" sort="Kageyama, Tsutomu" uniqKey="Kageyama T" first="Tsutomu" last="Kageyama">Tsutomu Kageyama</name>
<affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>Influenza Virus Research Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan</addr-line>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Influenza Virus Research Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ogawa Goto, Kiyoko" sort="Ogawa Goto, Kiyoko" uniqKey="Ogawa Goto K" first="Kiyoko" last="Ogawa-Goto">Kiyoko Ogawa-Goto</name>
<affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Nippi Research Institute of Biomatrix, Toride, Ibaraki, Japan</addr-line>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Nippi Research Institute of Biomatrix, Toride, Ibaraki</wicri:regionArea>
<wicri:noRegion>Ibaraki</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Multihartina, Pretty" sort="Multihartina, Pretty" uniqKey="Multihartina P" first="Pretty" last="Multihartina">Pretty Multihartina</name>
<affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>National Institute of Health Research and Development, Ministry of Health RI, Jakarta, Indonesia</addr-line>
</nlm:aff>
<country xml:lang="fr">Indonésie</country>
<wicri:regionArea>National Institute of Health Research and Development, Ministry of Health RI, Jakarta</wicri:regionArea>
<wicri:noRegion>Jakarta</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Setiawaty, Vivi" sort="Setiawaty, Vivi" uniqKey="Setiawaty V" first="Vivi" last="Setiawaty">Vivi Setiawaty</name>
<affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>National Institute of Health Research and Development, Ministry of Health RI, Jakarta, Indonesia</addr-line>
</nlm:aff>
<country xml:lang="fr">Indonésie</country>
<wicri:regionArea>National Institute of Health Research and Development, Ministry of Health RI, Jakarta</wicri:regionArea>
<wicri:noRegion>Jakarta</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Pangesti, Krisna Nur Andriana" sort="Pangesti, Krisna Nur Andriana" uniqKey="Pangesti K" first="Krisna Nur Andriana" last="Pangesti">Krisna Nur Andriana Pangesti</name>
<affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>National Institute of Health Research and Development, Ministry of Health RI, Jakarta, Indonesia</addr-line>
</nlm:aff>
<country xml:lang="fr">Indonésie</country>
<wicri:regionArea>National Institute of Health Research and Development, Ministry of Health RI, Jakarta</wicri:regionArea>
<wicri:noRegion>Jakarta</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hasegawa, Hideki" sort="Hasegawa, Hideki" uniqKey="Hasegawa H" first="Hideki" last="Hasegawa">Hideki Hasegawa</name>
<affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan</addr-line>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Division of Infectious Diseases Pathology, Department of Global Infectious Diseases, Tohoku Graduate School of Medicine, Sendai, Miyagi, Japan</addr-line>
</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Division of Infectious Diseases Pathology, Department of Global Infectious Diseases, Tohoku Graduate School of Medicine, Sendai, Miyagi</wicri:regionArea>
<wicri:noRegion>Miyagi</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">PLoS Pathogens</title>
<idno type="ISSN">1553-7366</idno>
<idno type="eISSN">1553-7374</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Mucosal immunoglobulins comprise mainly secretory IgA antibodies (SIgAs), which are the major contributor to pathogen-specific immune responses in mucosal tissues. These SIgAs are highly heterogeneous in terms of their quaternary structure. A recent report shows that the polymerization status of SIgA defines their functionality in the human upper respiratory mucosa. Higher order polymerization of SIgA (i.e., tetramers) leads to a marked increase in neutralizing activity against influenza viruses. However, the precise molecular mechanisms underlying the effects of SIgA polymerization remain elusive. Here, we developed a method for generating recombinant tetrameric monoclonal SIgAs. We then compared the anti-viral activities of these tetrameric SIgAs, which possessed variable regions identical to that of a broadly neutralizing anti-influenza antibody F045-092 against influenza A viruses, with that of monomeric IgG or IgA. The tetrameric SIgA showed anti-viral inhibitory activity superior to that of other forms only when the antibody exhibits low-affinity binding to the target. By contrast, SIgA tetramerization did not substantially modify anti-viral activity against targets with high-affinity binding. Taken together, the data suggest that tetramerization of SIgA improved target breadth, but not peak potency of antiviral functions of the broadly neutralizing anti-influenza antibody. This phenomenon presumably represents one of the mechanisms by which SIgAs present in human respiratory mucosa prevent infection by antigen-drifted influenza viruses. Understanding the mechanisms involved in cross neutralization of viruses by SIgAs might facilitate the development of vaccine strategies against viral infection of mucosal tissues.</p>
</div>
</front>
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</author>
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</author>
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</author>
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</author>
<author><name sortKey="Batten, Mr" uniqKey="Batten M">MR Batten</name>
</author>
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</author>
<author><name sortKey="Woof, Jm" uniqKey="Woof J">JM Woof</name>
</author>
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</author>
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</author>
<author><name sortKey="Basler, Cf" uniqKey="Basler C">CF Basler</name>
</author>
<author><name sortKey="Taubenberger, Jk" uniqKey="Taubenberger J">JK Taubenberger</name>
</author>
<author><name sortKey="Palese, P" uniqKey="Palese P">P Palese</name>
</author>
<author><name sortKey="Wilson, Ia" uniqKey="Wilson I">IA Wilson</name>
</author>
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</author>
<author><name sortKey="Latorre Margalef, N" uniqKey="Latorre Margalef N">N Latorre-Margalef</name>
</author>
<author><name sortKey="Stallknecht, De" uniqKey="Stallknecht D">DE Stallknecht</name>
</author>
<author><name sortKey="Krammer, F" uniqKey="Krammer F">F Krammer</name>
</author>
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</author>
<author><name sortKey="Nachbagauer, R" uniqKey="Nachbagauer R">R Nachbagauer</name>
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<author><name sortKey="Ermler, Me" uniqKey="Ermler M">ME Ermler</name>
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</author>
<author><name sortKey="Izikson, R" uniqKey="Izikson R">R Izikson</name>
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</author>
<author><name sortKey="Rajabhathor, A" uniqKey="Rajabhathor A">A Rajabhathor</name>
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<author><name sortKey="Treanor, Jj" uniqKey="Treanor J">JJ Treanor</name>
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</analytic>
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</analytic>
</biblStruct>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plospath</journal-id>
<journal-title-group><journal-title>PLoS Pathogens</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7366</issn>
<issn pub-type="epub">1553-7374</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">30605488</article-id>
<article-id pub-id-type="pmc">6317788</article-id>
<article-id pub-id-type="doi">10.1371/journal.ppat.1007427</article-id>
<article-id pub-id-type="publisher-id">PPATHOGENS-D-18-00987</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Physiology</subject>
<subj-group><subject>Immune Physiology</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Physiology</subject>
<subj-group><subject>Immune Physiology</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune System Proteins</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Immunology</subject>
<subj-group><subject>Immune System Proteins</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Immune System Proteins</subject>
<subj-group><subject>Antibodies</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject>
<subj-group><subject>Immunologic Techniques</subject>
<subj-group><subject>Immunoassays</subject>
<subj-group><subject>Enzyme-Linked Immunoassays</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>RNA viruses</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza viruses</subject>
<subj-group><subject>Influenza A virus</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Medical microbiology</subject>
<subj-group><subject>Microbial pathogens</subject>
<subj-group><subject>Viral pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza viruses</subject>
<subj-group><subject>Influenza A virus</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and health sciences</subject>
<subj-group><subject>Pathology and laboratory medicine</subject>
<subj-group><subject>Pathogens</subject>
<subj-group><subject>Microbial pathogens</subject>
<subj-group><subject>Viral pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza viruses</subject>
<subj-group><subject>Influenza A virus</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>Viral pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza viruses</subject>
<subj-group><subject>Influenza A virus</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject>
<subj-group><subject>Chemistry</subject>
<subj-group><subject>Chemical Reactions</subject>
<subj-group><subject>Polymerization</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject>
<subj-group><subject>Chemistry</subject>
<subj-group><subject>Polymer Chemistry</subject>
<subj-group><subject>Polymerization</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Recombinant Proteins</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>RNA viruses</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza Viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Medical Microbiology</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza Viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Pathology and Laboratory Medicine</subject>
<subj-group><subject>Pathogens</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza Viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Orthomyxoviruses</subject>
<subj-group><subject>Influenza Viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Infectious Diseases</subject>
<subj-group><subject>Viral Diseases</subject>
<subj-group><subject>Influenza</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject>
<subj-group><subject>Materials Science</subject>
<subj-group><subject>Materials</subject>
<subj-group><subject>Oligomers</subject>
<subj-group><subject>Dimers</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Physical Sciences</subject>
<subj-group><subject>Chemistry</subject>
<subj-group><subject>Polymer Chemistry</subject>
<subj-group><subject>Dimers</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody</article-title>
<alt-title alt-title-type="running-head">Production and characterization of tetrameric anti-influenza IgA bnAb</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Saito</surname>
<given-names>Shinji</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Sano</surname>
<given-names>Kaori</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-3820-9542</contrib-id>
<name><surname>Suzuki</surname>
<given-names>Tadaki</given-names>
</name>
<role content-type="http://credit.casrai.org/">Conceptualization</role>
<role content-type="http://credit.casrai.org/">Funding acquisition</role>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Project administration</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Visualization</role>
<role content-type="http://credit.casrai.org/">Writing – original draft</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ainai</surname>
<given-names>Akira</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-9100-758X</contrib-id>
<name><surname>Taga</surname>
<given-names>Yuki</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ueno</surname>
<given-names>Tomonori</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tabata</surname>
<given-names>Koshiro</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saito</surname>
<given-names>Kumpei</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wada</surname>
<given-names>Yuji</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ohara</surname>
<given-names>Yuki</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Takeyama</surname>
<given-names>Haruko</given-names>
</name>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Validation</role>
<xref ref-type="aff" rid="aff005"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Odagiri</surname>
<given-names>Takato</given-names>
</name>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kageyama</surname>
<given-names>Tsutomu</given-names>
</name>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ogawa-Goto</surname>
<given-names>Kiyoko</given-names>
</name>
<role content-type="http://credit.casrai.org/">Investigation</role>
<role content-type="http://credit.casrai.org/">Methodology</role>
<xref ref-type="aff" rid="aff004"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Multihartina</surname>
<given-names>Pretty</given-names>
</name>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Setiawaty</surname>
<given-names>Vivi</given-names>
</name>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-6339-915X</contrib-id>
<name><surname>Pangesti</surname>
<given-names>Krisna Nur Andriana</given-names>
</name>
<role content-type="http://credit.casrai.org/">Resources</role>
<xref ref-type="aff" rid="aff006"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hasegawa</surname>
<given-names>Hideki</given-names>
</name>
<role content-type="http://credit.casrai.org/">Funding acquisition</role>
<role content-type="http://credit.casrai.org/">Project administration</role>
<role content-type="http://credit.casrai.org/">Supervision</role>
<role content-type="http://credit.casrai.org/">Writing – review & editing</role>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>Department of Pathology, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>Influenza Virus Research Center, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>Division of Infectious Diseases Pathology, Department of Global Infectious Diseases, Tohoku Graduate School of Medicine, Sendai, Miyagi, Japan</addr-line>
</aff>
<aff id="aff004"><label>4</label>
<addr-line>Nippi Research Institute of Biomatrix, Toride, Ibaraki, Japan</addr-line>
</aff>
<aff id="aff005"><label>5</label>
<addr-line>Department of Life Science and Medical Bioscience, Waseda University, Shinjuku, Tokyo, Japan</addr-line>
</aff>
<aff id="aff006"><label>6</label>
<addr-line>National Institute of Health Research and Development, Ministry of Health RI, Jakarta, Indonesia</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Thomas</surname>
<given-names>Paul G.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>St. Jude Children's Research Hospital, UNITED STATES</addr-line>
</aff>
<author-notes><fn fn-type="COI-statement" id="coi001"><p>National Institute of Infectious Diseases and Nippi, Inc. have filed patents regarding construction and use of tetrameric SIgA (application no. PCT/JP2015/070742). SS, TS, AA, YT, TU, KOG and HH are named as inventors on the application. YT, TU, and KOG are employees of Nippi, Inc.</p>
</fn>
<corresp id="cor001">* E-mail: <email>tksuzuki@nih.go.jp</email>
(TS); <email>hasegawa@nih.go.jp</email>
(HH)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>3</day>
<month>1</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>1</month>
<year>2019</year>
</pub-date>
<volume>15</volume>
<issue>1</issue>
<elocation-id>e1007427</elocation-id>
<history><date date-type="received"><day>15</day>
<month>5</month>
<year>2018</year>
</date>
<date date-type="accepted"><day>22</day>
<month>10</month>
<year>2018</year>
</date>
</history>
<permissions><copyright-statement>© 2019 Saito et al</copyright-statement>
<copyright-year>2019</copyright-year>
<copyright-holder>Saito et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="ppat.1007427.pdf"></self-uri>
<abstract><p>Mucosal immunoglobulins comprise mainly secretory IgA antibodies (SIgAs), which are the major contributor to pathogen-specific immune responses in mucosal tissues. These SIgAs are highly heterogeneous in terms of their quaternary structure. A recent report shows that the polymerization status of SIgA defines their functionality in the human upper respiratory mucosa. Higher order polymerization of SIgA (i.e., tetramers) leads to a marked increase in neutralizing activity against influenza viruses. However, the precise molecular mechanisms underlying the effects of SIgA polymerization remain elusive. Here, we developed a method for generating recombinant tetrameric monoclonal SIgAs. We then compared the anti-viral activities of these tetrameric SIgAs, which possessed variable regions identical to that of a broadly neutralizing anti-influenza antibody F045-092 against influenza A viruses, with that of monomeric IgG or IgA. The tetrameric SIgA showed anti-viral inhibitory activity superior to that of other forms only when the antibody exhibits low-affinity binding to the target. By contrast, SIgA tetramerization did not substantially modify anti-viral activity against targets with high-affinity binding. Taken together, the data suggest that tetramerization of SIgA improved target breadth, but not peak potency of antiviral functions of the broadly neutralizing anti-influenza antibody. This phenomenon presumably represents one of the mechanisms by which SIgAs present in human respiratory mucosa prevent infection by antigen-drifted influenza viruses. Understanding the mechanisms involved in cross neutralization of viruses by SIgAs might facilitate the development of vaccine strategies against viral infection of mucosal tissues.</p>
</abstract>
<abstract abstract-type="summary"><title>Author summary</title>
<p>SIgAs exist as mainly dimers and tetramers and play critical roles in mucosal immune responses against influenza. Detailed characterization of these anti-viral SIgA is important for better understanding of the mechanisms underlying anti-viral immunity. Here, we describe a means of generating a recombinant tetrameric monoclonal SIgA to enable exhaustive characterization of tetrameric SIgAs. The tetrameric monoclonal SIgA possessing variable regions of anti-influenza viruses broadly neutralizing antibody show that tetramerization of SIgA improves target breadth, but not the peak potency, of their anti-viral functions. These results broaden our knowledge about the fundamental role of SIgA tetramerization in anti-viral humoral response at the human respiratory mucosa.</p>
</abstract>
<funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100009619</institution-id>
<institution>Japan Agency for Medical Research and Development</institution>
</institution-wrap>
</funding-source>
<award-id>JP18fk0108051</award-id>
<principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-3820-9542</contrib-id>
<name><surname>Suzuki</surname>
<given-names>Tadaki</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award002"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/100009619</institution-id>
<institution>Japan Agency for Medical Research and Development</institution>
</institution-wrap>
</funding-source>
<award-id>JP18fk0108012</award-id>
<principal-award-recipient><name><surname>Hasegawa</surname>
<given-names>Hideki</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award003"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001691</institution-id>
<institution>Japan Society for the Promotion of Science</institution>
</institution-wrap>
</funding-source>
<award-id>17K08386</award-id>
<principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-3820-9542</contrib-id>
<name><surname>Suzuki</surname>
<given-names>Tadaki</given-names>
</name>
</principal-award-recipient>
</award-group>
<funding-statement>The work was supported in part by the Emerging/Re-emerging Infectious Diseases Project of Japan, from the Japan Agency for Medical Research and Development, AMED under Grant Number JP18fk0108012 and JP18fk0108051; J-PRIDE from AMED under Grant Number JP18fm0208002; grants for Scientific Research from the Ministry of Education, Culture, Science, Sports and Technology (MEXT) of Japan (17K08386). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="5"></fig-count>
<table-count count="1"></table-count>
<page-count count="23"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>The B12 mAb sequences reported in this paper have been deposited in the NCBI database (Heavy chain variable region, MG904946; Light chain variable region, MG904947). <ext-link ext-link-type="uri" xlink:href="https://www.ncbi.nlm.nih.gov/nuccore/MG904946.1/">https://www.ncbi.nlm.nih.gov/nuccore/MG904946.1/</ext-link>
<ext-link ext-link-type="uri" xlink:href="https://www.ncbi.nlm.nih.gov/nuccore/MG904947">https://www.ncbi.nlm.nih.gov/nuccore/MG904947</ext-link>
Other relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>The B12 mAb sequences reported in this paper have been deposited in the NCBI database (Heavy chain variable region, MG904946; Light chain variable region, MG904947). <ext-link ext-link-type="uri" xlink:href="https://www.ncbi.nlm.nih.gov/nuccore/MG904946.1/">https://www.ncbi.nlm.nih.gov/nuccore/MG904946.1/</ext-link>
<ext-link ext-link-type="uri" xlink:href="https://www.ncbi.nlm.nih.gov/nuccore/MG904947">https://www.ncbi.nlm.nih.gov/nuccore/MG904947</ext-link>
Other relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
<affiliations><list><country><li>Indonésie</li>
<li>Japon</li>
</country>
<region><li>Région de Kantō</li>
</region>
<settlement><li>Tokyo</li>
</settlement>
</list>
<tree><country name="Japon"><region name="Région de Kantō"><name sortKey="Saito, Shinji" sort="Saito, Shinji" uniqKey="Saito S" first="Shinji" last="Saito">Shinji Saito</name>
</region>
<name sortKey="Ainai, Akira" sort="Ainai, Akira" uniqKey="Ainai A" first="Akira" last="Ainai">Akira Ainai</name>
<name sortKey="Hasegawa, Hideki" sort="Hasegawa, Hideki" uniqKey="Hasegawa H" first="Hideki" last="Hasegawa">Hideki Hasegawa</name>
<name sortKey="Hasegawa, Hideki" sort="Hasegawa, Hideki" uniqKey="Hasegawa H" first="Hideki" last="Hasegawa">Hideki Hasegawa</name>
<name sortKey="Kageyama, Tsutomu" sort="Kageyama, Tsutomu" uniqKey="Kageyama T" first="Tsutomu" last="Kageyama">Tsutomu Kageyama</name>
<name sortKey="Odagiri, Takato" sort="Odagiri, Takato" uniqKey="Odagiri T" first="Takato" last="Odagiri">Takato Odagiri</name>
<name sortKey="Ogawa Goto, Kiyoko" sort="Ogawa Goto, Kiyoko" uniqKey="Ogawa Goto K" first="Kiyoko" last="Ogawa-Goto">Kiyoko Ogawa-Goto</name>
<name sortKey="Ohara, Yuki" sort="Ohara, Yuki" uniqKey="Ohara Y" first="Yuki" last="Ohara">Yuki Ohara</name>
<name sortKey="Saito, Kumpei" sort="Saito, Kumpei" uniqKey="Saito K" first="Kumpei" last="Saito">Kumpei Saito</name>
<name sortKey="Saito, Shinji" sort="Saito, Shinji" uniqKey="Saito S" first="Shinji" last="Saito">Shinji Saito</name>
<name sortKey="Sano, Kaori" sort="Sano, Kaori" uniqKey="Sano K" first="Kaori" last="Sano">Kaori Sano</name>
<name sortKey="Sano, Kaori" sort="Sano, Kaori" uniqKey="Sano K" first="Kaori" last="Sano">Kaori Sano</name>
<name sortKey="Suzuki, Tadaki" sort="Suzuki, Tadaki" uniqKey="Suzuki T" first="Tadaki" last="Suzuki">Tadaki Suzuki</name>
<name sortKey="Tabata, Koshiro" sort="Tabata, Koshiro" uniqKey="Tabata K" first="Koshiro" last="Tabata">Koshiro Tabata</name>
<name sortKey="Taga, Yuki" sort="Taga, Yuki" uniqKey="Taga Y" first="Yuki" last="Taga">Yuki Taga</name>
<name sortKey="Takeyama, Haruko" sort="Takeyama, Haruko" uniqKey="Takeyama H" first="Haruko" last="Takeyama">Haruko Takeyama</name>
<name sortKey="Ueno, Tomonori" sort="Ueno, Tomonori" uniqKey="Ueno T" first="Tomonori" last="Ueno">Tomonori Ueno</name>
<name sortKey="Wada, Yuji" sort="Wada, Yuji" uniqKey="Wada Y" first="Yuji" last="Wada">Yuji Wada</name>
</country>
<country name="Indonésie"><noRegion><name sortKey="Multihartina, Pretty" sort="Multihartina, Pretty" uniqKey="Multihartina P" first="Pretty" last="Multihartina">Pretty Multihartina</name>
</noRegion>
<name sortKey="Pangesti, Krisna Nur Andriana" sort="Pangesti, Krisna Nur Andriana" uniqKey="Pangesti K" first="Krisna Nur Andriana" last="Pangesti">Krisna Nur Andriana Pangesti</name>
<name sortKey="Setiawaty, Vivi" sort="Setiawaty, Vivi" uniqKey="Setiawaty V" first="Vivi" last="Setiawaty">Vivi Setiawaty</name>
</country>
</tree>
</affiliations>
</record>
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